The invention described herein relates to the use of L-carnitine and alkanoyl L-carnitines in the preparation of medicaments useful in the treatment of tumours, particularly in combination with anticancer agents for the treatment of tumours.
It is well-known that the use of anticancer agents in human therapy causes a large number of toxic or side effects which may be life-threatening for the patients. These complications, in fact, may lead to a reduction in the doses of the agents, and occasionally to discontinuation of the therapy itself.
Reduction of the dose or discontinuation of the therapy in many cases causes a deterioration of the individual""s general condition because it favours the development of relapses, with consequences which are sometimes fatal for the patient.
Another very important and strongly felt aspect in the hospital setting and among the families of oncological patients is the concept of xe2x80x9cimproving the quality of lifexe2x80x9d of the patients under treatment.
It is equally well known that patients undergoing regular polychemotherapy for cancer are subject to a substantial weight loss.
The growing number and importance of the anticancer agents used in human therapy, the main limitation of which continues to be the occurrence of toxic or side effects, mean that this problem is still a matter for considerable concern.
Thus, the discovery of new agents or new, appropriate combinations of different agents capable of substantially reducing the toxic or side effects caused by anticancer agents used in human therapy is much to be desired.
Previous uses of L-carnitine in combination with anticancer agents are already known.
In experimental animal models, it has been demonstrated that rats treated with doxorubicin alone show a greater weight loss than a group of rats treated with the same substance in combination with L-carnitine (Senekowitsch R, Lohninger A, Kriegel H., Staniek H., Krieglsteiner H. P., Kaiser E. Protective effects of carnitine on adriamycin toxicity to heart. In: Kaiser E., Lohninger A., (eds.). Carnitine: its role in lung and heart disorders: 126-137. Karger, Basel-New York, 1987).
U.S. Pat. No. 4,713,370 describes the use of carnitine in combination with cytostatic agents such as daunomycin, N-acetyl-daunomycin and daunomycin oxime to reduce the cardiac toxicity of these compounds. U.S. Pat. No. 4,267,163 describes the use of carnitine in combination with cytostatic agents such as adriamycin, adriamycin-14-octanoate, 4xe2x80x2-epi-adriamycin, adriamycin beta-anomer and 4xe2x80x2-epi-adriamycin gamma-anomer to reduce the cardiac toxicity of these compounds. U.S. Pat. No. 4,751,242 describes the use of acetyl L-carnitine for the therapeutic treatment of peripheral neuropathies.
Other studies have addressed the evaluation of the protective effects of carnitines on anthracycline-induced cardiac toxicity (Neri B., Comparini T., Milani A., Torcia M., Clin. Trial J. 20, 98-103, 1983; De Leonardis V., De Scaizi M., Neri B., et al. Int. J. Clin. Pharm. Res. 70, 307-311, 1987).
The patent and bibliographical references cited above demonstrate that many efforts have been made in an attempt to reduce the toxic or side effects of anticancer agents, without, however, solving this serious problem in a satisfactory manner.
Carboplatin is a structural analogue of cisplatin and its associated nephrotoxicity, though by no means negligible, is less than that of cisplatin.
Vincristine is a well-known anticancer agent which has toxic effects, particularly at the level of the immune system.
Taxol is a natural extract, first isolated from the bark of Taxus breuifolia, with anticancer properties and has proved neurotoxic and myelotoxic in human subjects. It is used for the treatment of tumours resistant to platinum therapy, but gives rise to greater cumulative toxicity in the peripheral nervous system. It has also been ascertained that taxol induces neutropenia in the subjects treated (Rowinsky e al.; Semin. Oncol. (Aug. 20, 1993 (4 suppl 3), 1-15; Onetto e al. J. Natl. Cancer Inst. Monogr. (1993); (15):131-9).
Bleomycin is typically used in young patients with testicular cancer, lymphoma, and other types of tumours. The pulmonary toxicity of bleomycin is characterised by destruction of the alveolar epithelial barrier and the consequent intra-alveolar proliferation of fibroblasts and deposition of extracellular matrix components (Karam H et al.; Cell Biol. Toxicol (1998 Feb);14(1):13-22). Type 2 pneumocytes are not capable of regenerating the damaged or lost epithelium.
One of the general problems of pharmacological therapy is the therapeutic index of the agents, that is to say the ratio of the therapeutically effective dose to the toxic dose, or, at any rate, the dose that gives rise to the onset of side effects.
The medical community still perceives the need for therapeutic regimens which allow the patient to face up to the treatment, which, in the case of anticancer chemotherapy is particularly hard to support, while at the same time conserving an acceptable quality of life. These considerations also apply to the therapeutic treatment of animals, for instance, so-called pets.
The natural tendency to reduce the doses, and thus the use of pharmaceutical forms suitable for therapeutically useful administrations without obliging the patient to take the agents too often, contrasts with the minimum effective doses typical of each anticancer agent.
Surprisingly, it has been found that the co-ordinated usexe2x80x94this term will be precisely defined belowxe2x80x94of an anticancer agent and L-carnitine or an alkanoyl L-carnitine, as defined below, exerts an unexpected synergistic effect on the activity of the anticancer agent.
In the context of the invention described herein, it has also been found, in an entirely unexpected way, that the co-ordinated use of a therapeutically effective amount of an anticancer agent, in particular taxol, carboplatin, bleomycin and vincristine, and a detoxifying amount of L-carnitine or of an alkanoyl L-carnitine, in which the linear or branched alkanoyl has 2-8 carbon atoms, or one its pharmacologically acceptable salts, affords a potent protective effect against the toxicity and side effects of the anticancer agent, without impairing its efficacy, thus giving rise, amongst other things, to a substantial improvement in the quality of life and a prolonging of life itself in the subjects treated, whether human subjects or animals.
It has also been found that said coordinated use has an inhibitory effect on tumour metastases.
Therefore one object of the invention described herein is the use the compound of formula (I): 
where R is hydrogen or an alkanoyl group with 2 to 8 carbon atoms, and Xxe2x88x92 represents the anion of a pharmaceutically acceptable salt, for the preparation of a medicament comprising an anticancer agent, characterised in that said compound produces an synergistic effect on the activity of the anticancer agent.
Also an object of the invention described herein is the co-ordinated use the compound of formula (I) according to which the side effects of the anticancer agent in said medicament are substantially reduced.
A further object of the invention described herein is the use the compound of formula (I) in the preparation of a medicament useful for inhibiting metastases.
Yet another object of the invention described herein are combinations the compound of formula (I) with anticancer agents and the related pharmaceutical compositions.
The well known lack of toxic or side effects of alkanoyl L-carnitines makes the use of these compounds particularly safe even for long periods of treatment, for the prevention or treatment of toxic or side effects, such as weight loss, heart, kidney and central nervous system damage, peripheral nervous system damage, particularly neuropathy or neutropenia caused by taxol, or lung damage induced by bleomycin.
The implementation of the invention described herein also contributes to improving the quality of life of the patients treated; one need only think of the physical suffering caused by peripheral neuropathy, neutropenia, respiratory complications or debilitation due to weight loss caused by these agents.
These and other objects of the invention described herein will be described in detail in the embodiment forms of the invention, also by means of examples.
In the context of the invention described herein, the terms xe2x80x9cantineoplasticxe2x80x9d, xe2x80x9canticancerxe2x80x9d and xe2x80x9cantiproliferativexe2x80x9d are to be understood as being essentially synonymous.
In the context of the invention described herein, what is meant by xe2x80x9ccoordinated usexe2x80x9d of the aforesaid compounds is, indifferently, either (i) co-administration, i.e. the substantially simultaneous or sequential administration of L-carnitine or an alkanoyl L-carnitines or one of its pharmacologically acceptable salts and of an anticancer agent, or (ii) the administration of a composition comprising the aforesaid active ingredients in combination and in a mixture, in addition to optional pharmaceutically acceptable excipients and/or vehicles.
The invention described herein thus covers both the co-administration of L-carnitine or an alkanoyl L-carnitine or one of its pharmacologically acceptable salts of formula (I) and of the anticancer agent, and pharmaceutical compositions, which can be administered orally, parenterally or nasally, including controlled-release forms, comprising the two active ingredients in a mixture. Preferably, the alkanoyl L-carnitine is selected from the group consisting of acetyl L-carnitine (hereinafter abbreviated to ALC or Alcar), propionyl L-carnitine (hereinafter abbreviated to PLC), butyryl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine, or one of their pharmacologically acceptable salts. The ones preferred are acetyl L-carnitine, propionyl L-carnitine and butyryl L-carnitine.
Though clear from the following detailed description of the invention, one can also envisage the co-ordinated use of an anticancer agent, such as taxol, acetyl L-carnitine and propionyl L-carnitine, or of bleomycin and acetyl L-carnitine, orxe2x80x94a further possibilityxe2x80x94of acetyl L-carnitine and taxol or carboplatin or vincristine. In all these embodiments, L-carnitine can be used in the co-ordinated use.
Co-administration also means a package, or manufactured article, comprising distinct administration forms of L-carnitine or one of the aforesaid alkanoyl L-carnitines, or one of their pharmacologically acceptable salts and of an anticancer agent, accompanied by instructions for the coordinated simultaneous or time-scheduled intake of the active ingredients according to a dosage regimen established by the primary care physician, on the basis of the patient""s condition.
What is meant by a pharmacologically acceptable salt of L-carnitine or of an alkanoyl L-carnitine is any salt of the latter with an acid that does not give rise to toxic or side effects. These acids are well known to pharmacologists and to experts in pharmaceutical technology.
Examples of pharmacologically acceptable salts of L-carnitine or of the alkanoyl L-carnitines, though not exclusively these, are chloride; bromide; iodide; aspartate; acid aspartate; citrate; acid citrate; tartrate; acid tartrate; phosphate; acid phosphate; fumarate; acid fumarate; glycerophosphate; glucose phosphate; lactate; maleate; acid maleate; mucate; orotate, oxalate; acid oxalate; sulphate; acid sulphate; trichloroacetate; trifluoroacetate; methane sulphonate; pamoate and acid pamoate.
One preferred form of daily dosing of L-carnitine or alkanoyl L-carnitine for clinical use is a composition comprising an amount of L-carnitine or an alkanoyl L-carnitine, preferably acetyl or propionyl L-carnitine, equivalent to 0.1 to 3 g, and preferably 0.5 to 3 g.
The invention described herein is advantageous in the prevention or treatment of toxic or side effects such as weight loss, heart, kidney and central nervous system damage, peripheral nervous system damage, peripheral neuropathy and particularly the myelosuppression and lung damage caused by the above-mentioned anticancer agents.
What is meant by substantially protective effect is the prevention, reduction or elimination of the side effect to a statistically significant extent.
The embodiment of the invention described herein also contributes to healing and to prolonging the lives of the patients thanks to the increase in therapeutic success due to the possibility of maintaining the scheduled treatment protocols or of increasing the doses of the chemotherapeutic agent, without having to discontinue the treatment due to contraindications.
A further benefit which is obtained with the invention described herein is related to the quality of life of the subjects treated; in fact, as already mentioned, the elimination or reduction of the physical suffering caused by a peripheral neuropathy or by debilitation due to weight loss favours the patient""s ability to be self-sufficient. From the economic standpoint, there are obvious savings in terms of the costs borne by hospital facilities or by the families for the patient""s care.
Myelosuppression is one of the toxic side effects that may manifest themselves as a result of administration of taxol, a chemotherapeutic agent used in the therapy of various tumours, for example, of the breast, ovaries, lungs (small cell and otherwise), head and neck (Slichenmeyer and Von Hoff: J. Clin. Pharmacol. (1990), 30, 770-778). The vehicle adopted for taxol, also in the commercial pharmaceutical forms (TAXOL(copyright), Bristol Myers Squibb), is a derivative of polyethoxylated castor oil, known commercially as Cremophor(copyright) EL and is capable of inducing histamine release and anaphylactoid reactions in the dog and in human subjects (Slichenmeyer and Von Hoff: ibid; Bury et al.: Allergy (1992), 47, 624-629; Hershkoviz et al.: J. Leukoc. Biol. (1994), 56, 495-501; Inokuma et al.: J. Vet. Med. Sci. (1994), 56, 45-49). In view of the fact that the marketed drug is vehicled in Cremophor(copyright) EL, the problem of the myelotoxicity relating to the preparation used in therapy has been tackled.
One of the most serious problems encountered in the course of proliferative diseases is the metastatic spread of the tumour, which sometimes advances to such an extent as to render useless the treatment of the primary tumour and itself becomes the cause of death.
In a first preferred embodiment of the invention described herein, L-carnitine, combined with an anticancer agent such as taxol, carboplatin or vincristine, ensures an extension of survival of the subject treated.
In a second embodiment of the invention described herein, acetyl L-carnitine has shown an unexpected degree of protective activity against taxol-induced side effects, such as peripheral neuropathy, myelosuppression and weight loss.
In a third embodiment of the invention described herein, acetyl L-carnitine has shown surprising antimetastatic activity when administered concomitantly with taxol, particularly in lung cancer.
According to another preferred embodiment of the invention described herein, propionyl L-carnitine has shown an unexpected synergistic effect in combination with taxol.
It has been found that taxol induces severe neutropenia with a nadir after the 3rd-4th injection of the compound.
When ALC is used according to the invention described herein, no adverse effects on the anticancer action of the drug are found.
ALC can be conveniently administered orally, without, for that reason, excluding other administration routes which an expert in the field may deem it advisable to adopt, particularly, by injection, to be administered concomitantly, for example, in the same infusion vial, with the anticancer agent, or in sequence, as established by the expert in the field.
Equally, propionyl L-carnitine (PLC) has shown a synergistic effect with the therapeutic activity of taxol.
It is therefore evidently advantageous to provide a ternary combination, also in separate dosage forms, or in some way combined, of acetyl L-carnitine as a protective agent, propionyl L-carnitine as a synergistic agent and taxol. This combination also comprises other anticancer agents which show a synergistic effect or induce substantially reduced side effects as a result of the combination according to the invention described herein. It may also be advantageous to add L-carnitine to the above-mentioned combination.
One specific object of the invention described herein is a pharmaceutical composition comprising a therapeutically effective amount of taxol together with a protective amount of acetyl L-carnitine and a synergistic amount of propionyl L-carnitine, in a mixture with pharmaceutically acceptable vehicles and/or excipients.
In a different embodiment, it is in any case advantageous to provide a binary combination of acetyl L-carnitine, as a protective agent, and bleomycin.
As regards those aspects relating to industrial applicability, the invention described herein also provides, in one of its possible embodiments, for a kit containing a) a pharmaceutical composition comprising a therapeutically effective amount of an anticancer agent; b) a pharmaceutical composition comprising at least one alkanoyl L-carnitine, as defined above, in an amount suitable for producing a synergistic effect with said anticancer agent; c) a pharmaceutical combination comprising at least one alkanoyl L-carnitine and/or L-carnitine, as defined above, in an amount suitable for producing a substantially protective action against the side effects of said anticancer agent. The kit according to the invention described herein may also be presented in the form of a) a pharmaceutical composition comprising a therapeutically effective amount of an anticancer agent; b) a pharmaceutical composition comprising at least one alkanoyl L-carnitine in an amount suitable for producing a synergistic effect with said anticancer agent. Alternatively, the kit according to the invention described herein may also be presented in the form of a) a pharmaceutical composition comprising a therapeutically effective amount of an anticancer agent; and b) a pharmaceutical composition comprising at least one alkanoyl L-carnitine and/or L-carnitine in an amount suitable for producing a substantially protective action against the side effects of said anticancer agent.
Specific examples of the above-mentioned kits refer to carboplatin, vincristine, taxol and bleomycin as the anticancer agents.
We shall now describe the ways of implementing the invention described herein with reference to the preferred embodiment, using taxol as the anticancer agent, acetyl L-carnitine as the substantially protective agent and propionyl L-carnitine as the substantially synergistic agent.
It remains understood that the expert in the field may complete the experimental protocols with his or her own general knowledge of the field in which he or she operates, possibly resorting to neighbouring sectors in case of need.
We report here below the results of the most significant experiments suitable for demonstrating the unexpected and surprising protective effect obtained by the combination of L-carnitine or its derivatives with the above-mentioned anticancer agents.